Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain.

AIMS: According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α-synuclein (α-syn) in the gastrointestinal tract and midbrain dopaminergic neurons. METHODS: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS-based rat model of gut inflammation in terms of α-syn pathology. RESULTS: Our data support the existence of pathogenic α-syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS-based rat model of gut inflammation to demonstrate (i) the appearance of P-α-syn inclusions in both Auerbach's and Meissner's plexuses (gut), (ii) an increase in α-syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD. CONCLUSION: These results strongly support the plausibility of Braak's hypothesis and emphasise the significance of peripheral inflammation and the gut-brain axis in initiating α-syn aggregation and transport to the substantia nigra, resulting in neurodegeneration.

Fecal biomarkers and micromorphological indicators of sheep penning and flooring at La Fortaleza pre-Hispanic site (Gran Canaria, Canary Islands).

This study explores the lipid content and micromorphological features of sediment samples from two dwelling structures at the pre-Hispanic site of La Fortaleza in Santa Lucía de Tirajana (Gran Canaria, Spain). Previous field identification of possible sedimentary excrements inside the dwellings motivated chromatographic fecal biomarker analysis and micromorphology. The micromorphological samples reveal a complex dung-rich stratified sequence involving different layers of mixed composition, including reworked dung, clay, wood ash, and domestic refuse. The results of the lipid analysis corroborate the fecal nature of the sample and indicate the source animal: sheep. Coupled with the field evidence, the data suggest that the deposit is anthropogenic and represents a sequence of floor foundations, dung floors, and domestic and architectural refuse. This study provides valuable taxonomic and site use data for the understanding of the aboriginal societies of the Canary Islands and shows the efficacy of combining field observations with high-resolution geoarchaeological methods.

Statistical inference with a manifold-constrained RNA velocity model uncovers cell cycle speed modulations.

Across a range of biological processes, cells undergo coordinated changes in gene expression, resulting in transcriptome dynamics that unfold within a low-dimensional manifold. Single-cell RNA-sequencing (scRNA-seq) only measures temporal snapshots of gene expression. However, information on the underlying low-dimensional dynamics can be extracted using RNA velocity, which models unspliced and spliced RNA abundances to estimate the rate of change of gene expression. Available RNA velocity algorithms can be fragile and rely on heuristics that lack statistical control. Moreover, the estimated vector field is not dynamically consistent with the traversed gene expression manifold. Here, we develop a generative model of RNA velocity and a Bayesian inference approach that solves these problems. Our model couples velocity field and manifold estimation in a reformulated, unified framework, so as to coherently identify the parameters of an autonomous dynamical system. Focusing on the cell cycle, we implemented VeloCycle to study gene regulation dynamics on one-dimensional periodic manifolds and validated using live-imaging its ability to infer actual cell cycle periods. We benchmarked RNA velocity inference with sensitivity analyses and demonstrated one- and multiple-sample testing. We also conducted Markov chain Monte Carlo inference on the model, uncovering key relationships between gene-specific kinetics and our gene-independent velocity estimate. Finally, we applied VeloCycle to in vivo samples and in vitro genome-wide Perturb-seq, revealing regionally-defined proliferation modes in neural progenitors and the effect of gene knockdowns on cell cycle speed. Ultimately, VeloCycle expands the scRNA-seq analysis toolkit with a modular and statistically rigorous RNA velocity inference framework.

Microstratigraphic, lipid biomarker and stable isotope study of a middle Palaeolithic combustion feature from Axlor, Spain.

Archaeological research has increasingly focused on studying combustion features as valuable sources of information regarding past technological and cultural aspects. The use of microstratigraphic and biomolecular techniques enables the identification of combustion residues and substrate components, and infer about past fire-related activities and the environments. Our study conducted on a combustion feature (Level N, ∼100 Ka) at the Axlor cave, a Middle Paleolithic site in northern Iberia, exemplifies the interdisciplinary approach to combustion features. Micromorphological features revealed depositional activities associated with occupations such as hearth rake-out and trampling. Through molecular (n-alkanes, n-alcohols, and n-fatty acids) and isotopic analysis (δ13C16:0 and δ13C18:0), we infer the good preservation of organic matter, the contributions of non-ruminant fats, and the dead-wood gathering strategies by Neanderthal groups. By combining microstratigraphic and biomolecular approaches, our study significantly contributes to the advancement of our current understanding of Neanderthal pyrotechnology.

Effector T Cells Promote Fibrosis in Corneal Transplantation Failure.

Purpose: To evaluate whether fibrosis contributes to corneal transplant failure and to determine whether effector CD4+ T cells, the key immune cells in corneal transplant rejection, play a direct role in fibrosis formation. Methods: Allogeneic corneal transplantation was performed in mice. Graft opacity was evaluated by slit-lamp biomicroscopy, and fibrosis was assessed by in vivo confocal microscopy. Expression of alpha-smooth muscle actin (α-SMA) in both accepted and failed grafts was assessed by real-time PCR and immunohistochemistry. Frequencies of graft-infiltrating CD4+ T cells, neutrophils, and macrophages were assessed using flow cytometry. In vitro, MK/T-1 corneal fibroblasts were co-cultured with activated CD4+CD25- effector T cells isolated from corneal transplant recipient mice, and α-SMA expression was quantified by real-time PCR and ELISA. Neutralizing antibody was used to evaluate the role of interferon gamma (IFN-γ) in promoting α-SMA expression. Results: The majority of failed grafts demonstrated clinical signs of fibrosis which became most evident at week 6 after corneal transplantation. Failed grafts showed higher expression of α-SMA as compared to accepted grafts. Flow cytometry analysis showed a significant increase in CD4+ T cells in failed grafts compared to accepted grafts. Co-culture of activated CD4+CD25- effector T cells with corneal fibroblasts led to an increase in α-SMA expression by fibroblasts. Inhibition of IFN-γ in culture significantly suppressed this increase in α-SMA expression as compared to immunoglobulin G control. Conclusions: Fibrosis contributes to graft opacity in corneal transplant failure and is mediated at least in part by effector CD4+ T cells via IFN-γ.

Sexting is not always wanted: consequences on satisfaction and the role of sexual coercion and online sexual victimization / El Sexting no siempre es deseado: consecuencias sobre la satisfación y el papel de la coerción sexual y la victimización sexual en línea

La comprensión del sexting como una nueva forma de comuni-cación interpersonal es cada vez mayor; sin embargo, poco se sabe sobre si la incidencia, correlatos y resultados del sexting varían en función de si se realiza de forma voluntaria o no. En este estudio no experimental, nos proponemos investigar la prevalencia, los predictores y las consecuencias del sexting entre 310 jóvenes españoles, que completaron una encuesta on-line sobre sus experiencias previas de sexting deseado y no deseado, coer-ción sexual y victimización sexual online, así como sus niveles de satisfac-ción sexual y vital. Los resultados mostraron que la mitad y un tercio de la muestra habían estado involucrados en comportamientos de sexting desea-dos y no deseados, respectivamente. Además, lacoerción sexual y la victi-mización sexual online predijeron una mayor probabilidad de participar en conductas sexuales no deseadas y, con ello, una disminución de la satisfac-ción vital. Por último, haber experimentado mayor coerción sexual se aso-ció con menor satisfacción vital al aumentar la probabilidad de sufrir victi-mización sexual online y de participar en conductas adicionales de sexting no deseado. Nuestros hallazgos muestran la importancia de discernir entre el sexting deseado y el no deseado y cómo el hacerlo de forma diferente condiciona los predictores y las consecuencias de este fenómeno.(AU)

The understanding of sexting as a new form of interpersonal communication is increasing; however, little is known about whether the incidence, correlates, and outcomes of sexting vary depending on whether such behavior is done willingly or not. In this non-experimental study, we aimed to investigate the prevalence, predictors, and consequences of sex-ting among 310 Spanish young adults, who completed an online survey re-garding their previous experiences of wanted and unwanted sexting behav-iors, their sexual coercion and online sexual victimization experiences, and their levels of sexual and life satisfaction. The results showed that more than half and one third of the sample had been involved in wanted and unwanted sexting behaviors, respectively. Additionally, sexual coercion and online sexual victimization predicted a higher probability of engaging in unwanted sexual behaviors and, with that, a decrease of life satisfaction. Finally, having experienced more instances of sexual coercion was associ-ated with lower life satisfaction by increasing the likelihood of suffering online sexual victimization experiences and engaging in additional unwant-ed sexting behaviors. Our findings show the importance of discerning be-tween wanted and unwanted sexting and how doing so differently condi-tions the predictors and consequences of this phenomena.(AU)

The novel gene, mtre-1 , is expressed downstream of MAB-3 and DMD-3 in the male tail tip at the termination of male tail tip retraction.

The development of the adult C. elegans male tail involves an extensive remodeling during the last larval stage where the pointed tail of the L4 male is converted into the blunt-ended adult tail with its collection of mechano-sensitive rays. The first step in this remodeling is the retraction of the four hypodermal cells of the tail tip to generate the blunt-ended tail. Male tail tip retraction is an excellent model for characterizing how upstream regulatory networks interact with the downstream cell biological effectors that drive morphogenetic changes in all animals. Previously, we've shown that two DM-domain transcription factors, MAB-3 and DMD-3 , are central regulators of male tail tip retraction. Using a microarray-based approach we have identified ~400 genes that are more highly expressed in the L4 male tail tip relative to the hermaphrodite L4 tail tip. The uncharacterized gene T05H10.3 , which we've named mtre-1 , was highly over-represented in the male tail tip vs. the hermaphrodite tail tip and was under-represented in mab-3 ; dmd-3 mutant male tail tips vs. wild-type male tail tips. A transcriptional reporter for mtre-1 shows clear expression in the male tail tip cells for a short period (~3 hours) at the end of retraction. This expression is dependent on the activity of MAB-3 and DMD-3 , since expression is reduced in dmd-3 single mutant males and absent in mab-3 ; dmd-3 mutant males. Finally, males homozygous for a putative null allele of mtre-1 display a phenotypically wild-type adult male tail, indicating that mtre-1 is not essential for male tail morphogenesis.

Advances in the Development of Carbonic Anhydrase Inhibitors as New Antiprotozoal Agents.

BACKGROUND: Parasitic diseases are a public health problem despite the existence of drugs for their treatment. These treatments have variable efficacy and, in some cases, serious adverse effects. There has been interest in the enzyme carbonic anhydrase (CA) in the last two decades since it is essential in the life cycle of various parasites due to its important participation in processes such as pyrimidine synthesis, HCO3- transport across cell membranes, and the maintenance of intracellular pH and ion transport (Na+, K+, and H+), among others. OBJECTIVE: In this review, CA was analyzed as a pharmacological target in etiological agents of malaria, American trypanosomiasis, leishmaniasis, amoebiasis, and trichomoniasis. The CA inhibitors´ design, binding mode, and structure-activity relationship are also discussed. CONCLUSION: According to this review, advances in discovering compounds with potent inhibitory activity suggest that CA is a candidate for developing new antiprotozoal agents.

Trial design of the MOTheR HDx study: a multicenter, open-label, prospective, randomized study to explore the morbidity and mortality in patients dialyzed with the Theranova HDx in comparison with online hemodiafiltration.

Background: Dialysis patients have been maintaining a high rate of cardiovascular morbidity and mortality. For this reason, it is to introduce necessary new technical advances in clinical practice. There is a relation between toxins retention and inflammation, mortality and morbidity. Medium cut-off (MCO) membranes are a new generation of membranes that allow the removal of a greater number of medium-sized molecules compared with high-flux hemodialysis (HF-HD), but retaining albumin. MCO membranes have an increased permeability and the presence of internal filtration. Because of these special properties, MCO generated a new concept of therapy called expanded HD (HDx). Until now, online hemodiafiltration (OL-HDF) has demonstrated its superiority, in terms of survival, compared with HF-HD. However, the comparison between OL-HDF and HDx remains an unsolved question. Methods: The MOTheR HDx study trial (NCT03714386) is an open-label, multicenter, prospective, 1:1 randomized, parallel-group trial designed to evaluate the efficacy and safety of HDx compared with OL-HDF in patients treated for dialysis in Spain for up to 36 months. The main endpoint is to determinate whether HDx is non inferior to OL-HDF at reducing the combined outcome of all-cause death and stroke (ischemic or hemorrhagic), acute coronary syndrome (angina and myocardial infarction), peripheral arterial disease (amputation or revascularization) and ischemic colitis (mesenteric thrombosis). Results: The trial has already started.

Numerical Study of the Plastic Zone at the Crack Front in Cylindrical Aluminum Specimens Subjected to Tensile Loads.

Cylindrical specimens are of great interest in analyzing mechanical elements' behavior and investigating phenomena with biaxial loads. It is necessary to identify the behavior of the crack front along the thickness to interpret these results, which are usually based on the hypothesis of a straight crack and the observation of the outer face of the crack front. Based on the work carried out on compact tension type specimens, this work proposes adapting this methodology to cylindrical specimens, adapting the previous finite element models. Cylindrical specimens provide an asymmetric behavior influenced by the radius, where the CT (compact tensile) specimen can be considered the extreme infinite radius case. Combinations of the load level and radius values help us simulate the crack's behavior under intermediate hypotheses between a plane crack theory and a three-dimensional one. The plastic strain around the crack front will be analyzed as a function of the thickness and the load level applied. The results allow us to validate the numerical methodology and establish the differentiated behaviors of the plastic zones close to the outer and inner radii.

Spanish cardiac catheterization and coronary intervention registry. 32nd official report of the Interventional Cardiology Association of the Spanish Society of Cardiology (1990-2022).

INTRODUCTION AND OBJECTIVES: This article presents the annual activity report of the Interventional Cardiology Association of the Spanish Society of Cardiology (ACI-SEC) for the year 2022. METHODS: All Spanish centers with catheterization laboratories were invited to participate. Data were collected online and were analyzed by an external company in collaboration with the members of the board of the ACI-SEC. RESULTS: A total of 111 centers participated. The number of diagnostic studies increased by 4.8% compared with 2021, while that of percutaneous coronary interventions (PCI) remained stable. PCIs on the left main coronary artery increased by 22%. The radial approach continued to be preferred for PCI (94.9%). There was an upsurge in the use of drug-eluting balloons, as well as in intracoronary imaging techniques, which were used in 14.7% of PCIs. The use of pressure wires also increased (6.3% vs 2021) as did plaque modification techniques. Primary PCI continued to grow and was the most frequent treatment (97%) in ST-segment elevation myocardial infarction. Most noncoronary procedures maintained their upward trend, particularly percutaneous aortic valve implantation, atrial appendage closure, mitral/tricuspid edge-to-edge therapy, renal denervation, and percutaneous treatment of pulmonary arterial disease. CONCLUSIONS: The Spanish cardiac catheterization and coronary intervention registry for 2022 reveals a rise in the complexity of coronary disease, along with a notable growth in procedures for valvular and nonvalvular structural heart disease.

Compound-specific carbon isotope analysis of short-chain fatty acids from Pine tissues: characterizing paleo-fire residues and plant exudates.

Different types of plant tissues and resin can account for the wax lipids found in sedimentary contexts and archaeological samples. Consequently, there is increasing research to characterize the fatty acid carbon isotope ratios of different plant anatomical parts and their plant exudates (resin). With the aim to explore isotopic differences between plant tissues, state of the fine organic matter, effect of thermal degradation, and to identify plant residues we measured the δ13C values of short-chain fatty acids (δ13C16:0 and δ13C18:0) in: i) dead and fresh (collected and immediately dried) pine needles and branches (Pinus canariensis) and pine resin from laboratory-controlled heating experiments and ii) sediment and charred pine tissue samples from a wild pine forest fire. Our results are compared to previously published experimental open-air fire experiments and pine-fuelled archaeological combustion features. We found that for both fatty acid types, there are differences in δ13C signatures among anatomical parts and initial moisture content. These data allow us to characterize the isotopic signature of pine tissue and the effect of degradation on isotopic biomarkers, as well as to estimate combustion temperatures in pine-fuelled anthropogenic fires. Supplementary Information: The online version contains supplementary material available at 10.1007/s12520-023-01815-3.

Neurogenesis redirects ß-catenin from adherens junctions to the nucleus to promote axonal growth.

Here, we show that, in the developing spinal cord, after the early Wnt-mediated Tcf transcription activation that confers dorsal identity to neural stem cells, neurogenesis redirects ß-catenin from the adherens junctions to the nucleus to stimulate Tcf-dependent transcription in a Wnt-independent manner. This new ß-catenin activity regulates genes implicated in several aspects of contralateral axon growth, including axon guidance and adhesion. Using live imaging of ex-vivo chick neural tube, we showed that the nuclear accumulation of ß-catenin and the rise in Tcf-dependent transcription both initiate before the dismantling of the adherens junctions and remain during the axon elongation process. Notably, we demonstrated that ß-catenin activity in post-mitotic cells depends on TCF7L2 and is central to spinal commissural axon growth. Together, our results reveal Wnt-independent Tcf/ß-catenin regulation of genes that control the growth and guidance of commissural axons in chick spinal cord.

Assessment of endocrine disruptor pollutants and their metabolites in environmental water samples using a sustainable natural deep eutectic solvent-based analytical methodology.

In this work, an evaluation of the occurrence of fifteen phthalates, four metabolites and one adipate in different groundwater, seawater and wastewater samples has been carried out due to their relevance on human health as they act as endocrine disruptors. For this purpose, a sustainable, fast and easy-handling vortex-assisted liquid-liquid microextraction method using a natural hydrophobic deep eutectic solvent based on menthol and carvacrol as extraction agent, combined with ultra-high performance liquid chromatography-mass spectrometry technique, has been developed and applied for the first time. An optimization was performed to evaluate four important factors affecting the extraction performance, and an analytical validation was carried out in terms of matrix effect, linearity, extraction efficiency, and sensitivity. Recovery values were obtained in the range 72-119% for all analytes (except for monoethyl phthalate: 61.1-72.3%) with relative standard deviation values lower than 17%. Limits of quantification were found between 0.91 and 8.09 µg L-1. As a result of the assessment of 31 different environmental water samples, monoethyl phthalate, diethyl phthalate, dibutyl phthalate and bis (2-ethylhexyl) phthalate were detected and quantified at different concentrations in the range 2.59-21.17 µg L-1 in 6 samples, and diallyl phthalate, butyl benzyl phthalate, dipentyl phthalate, dicyclohexyl phthalate, dihexyl phthalate and bis (2-ethylhexyl) adipate were detected in 20 more, showing the exposition of the population to these hazardous substances.

Colorectal cancer: a qualitative study of coping strategies used by survivors, with associated social determinants.

BACKGROUND: Colorectal cancer survivors have to develop coping strategies during the diagnosis and survivorship period. This study aims to identify coping strategies in patients with colorectal cancer, in particular the differences between coping strategies during the disease and throughout survival. It also aims to investigate the impact of some social determinants on coping strategies and critically reflect on the influence of positive psychology. METHODS: Qualitative study with in-depth interviews of a purposive sample of 21 colorectal cancer survivors in Majorca (Spain), developed between 2017-2019. Data was analysed using interpretive thematic analysis. RESULTS: We observed different coping strategies during the stages of disease and survival. However, striving toward acceptance and adaptation when facing difficulties and uncertainty, predominate in both stages. Confrontational attitudes are also considered important, as well as encouraging positive rather than negative feelings, which are considered unhelpful and to be avoided. CONCLUSIONS: Although coping during illness and survival can be classified into common categories (problem and emotion-centred strategies), the challenges of these stages are faced differently. Age, gender and the cultural influence of positive psychology strongly influence both stages and strategies.

Microglial Caspase-3 is essential for modulating hippocampal neurogenesis.

Adult hippocampal neurogenesis (AHN) is a process involved in numerous neurodegenerative diseases. Many researchers have described microglia as a key component in regulating the formation and migration of new neurons along the rostral migratory stream. Caspase-3 is a cysteine-aspartate-protease classically considered as one of the main effector caspases in the cell death program process. In addition to this classical function, we have identified the role of this protein as a modulator of microglial function; however, its action on neurogenic processes is unknown. The aim of the present study is to identify the role of Caspase-3 in neurogenesis-related microglial functions. To address this study, Caspase-3 conditional knockout mice in the microglia cell line were used. Using this tool, we wanted to elucidate the role of this protein in microglial function in the hippocampus, the main region in which adult neurogenesis takes place. After the reduction of Caspase-3 in microglia, mutant mice showed a reduction of microglia in the hippocampus, especially in the dentate gyrus region, a region inherently associated to neurogenesis. In addition, we found a reduction in doublecortin-positive neurons in conditional Caspase-3 knockout mice, which corresponds to a reduction in neurogenic neurons. Furthermore, using high-resolution image analysis, we also observed a reduction in the phagocytic capacity of microglia lacking Caspase-3. Behavioral analysis using object recognition and Y-maze tests showed altered memory and learning in the absence of Caspase-3. Finally, we identified specific microglia located specifically in neurogenic niche positive for Galectin 3 which colocalized with Cleaved-Caspase-3 in control mice. Taken together, these results showed the essential role of Caspase-3 in microglial function and highlight the relevant role of this specific microglial phenotype in the maintenance of AHN in the hippocampus.

Recent advances in the development of methyltransferase (MTase) inhibitors against (re)emerging arboviruses diseases dengue and Zika.

Emerging and/or re-emerging viral diseases such as dengue and Zika are a worldwide concern. Therefore, new antiviral therapeutics are necessary. In this sense, a non-structural protein with methyltransferase (MTase) activity is an attractive drug target because it plays a crucial role in dengue and Zika virus replication. Different drug strategies such as virtual screening, molecular docking, and molecular dynamics have identified new inhibitors that bind on the MTase active site. Therefore, in this review, we analyze MTase inhibitors, including S-adenosyl-L-methionine (SAM), S-adenosyl-l-homocysteine (SAH) and guanosine-5'-triphosphate (GTP) analogs, nitrogen-containing heterocycles (pyrimidine, adenosine, and pyridine), urea derivatives, and natural products. Advances in the design of MTase inhibitors could lead to the optimization of a possible single or broad-spectrum antiviral drug against dengue and Zika virus.

Monitoring of the presence of plasticizers and effect of temperature and storage time in bottled water using a green liquid-liquid microextraction method.

In this work, a natural deep eutectic solvent was used for the liquid-liquid microextraction of fourteen phthalates and one adipate from bottled waters. The methodology was validated in terms of matrix effect, linearity, recovery, and limits of quantification (LOQs). Optimum extraction conditions (10 mL of water at pH 8.0 with 100 µL of thymol: menthol 2:1 (n/n) as solvent) provided satisfactory determination coefficients (≥ 0.9977), recovery values (82-127%), and LOQs (0.018-0.523 µg/L). The effects of temperature and storage time on plasticizer presence were studied for 36 different brands stored at 4 °C, room temperature, and 45 °C, and analyzed at 0, 24, 48, 72 h, and 1 week. Only diethyl-, dibutyl-, bis-(2-ethylhexyl) phthalates, and bis-(2-ethylhexyl) adipate were detected. The results showed that there is no relationship between the storage conditions, the bottle material or water carbonation, and the occurrence of these plasticizers, suggesting that residues are introduced during production or by the water supply. The estimated daily intake was lower than the total daily intake set by the European Food Safety Authority.

Assessment of pesticide residues contamination in cereals and pseudo-cereals marketed in the Canary Islands.

In this work, the development of an analytical method for the evaluation of a wide variety of pesticide residues in cereals and pseudo-cereals widely consumed has been carried out. A QuEChERS method was used as extraction and clean-up procedure prior to separation and quantification of the target analytes by ultra-high performance liquid chromatography coupled to mass spectrometry using a single quadrupole-time-of-flight analyser. The methodology was validated for oat, rye, spelt, barley and quinoa matrices, following the European Commission guidelines (SANTE/11312/2021), achieving good absolute recovery values in the range 60-124% with relative standard deviation values lower than 20% and providing limits of quantification of the method in the low mg/kg range, in accordance with the maximum residue limits established by European policies. Finally, considering the importance of cereals in general population diet, the analysis of 60 samples was carried out in order to assure their safe consumption.